CN105061397B - A kind of c-type crystal formation of Ceritinib and preparation method and application - Google Patents
A kind of c-type crystal formation of Ceritinib and preparation method and application Download PDFInfo
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- CN105061397B CN105061397B CN201510486961.2A CN201510486961A CN105061397B CN 105061397 B CN105061397 B CN 105061397B CN 201510486961 A CN201510486961 A CN 201510486961A CN 105061397 B CN105061397 B CN 105061397B
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- ceritinib
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides a kind of c-type crystal formation of Ceritinib.There is characteristic peak at 2 θ angles is 4.9 °, 9.4 °, 9.9 °, 12.2 °, 13.7 °, 14.2 °, 14.4 °, 14.9 °, 15.6 °, 16.5 °, 17.0 °, 17.7 °, 18.9 °, 20.6 °, 22.0 °, 25.0 °, 26.6 °, 25.9 ° and 28.5 ° in the X ray powder diffraction patterns that the c-type crystal formation of the Ceritinib is obtained using Cu K alpha ray measurements.The present invention also provides the preparation method and application of the c-type crystal formation of above-mentioned Ceritinib.The c-type crystal formation crystallinity of the Ceritinib of the present invention is high, water solubility is high, and its preparation method is simple, is easily controlled, and c-type crystal formation, and favorable reproducibility is easily prepared, and significantly improve the oral administration biaavailability of Ceritinib.
Description
Technical field
The present invention relates to c-type crystal formation of a kind of Ceritinib and preparation method and application, belongs to medicine novel crystal forms technology
Field.
Background technology
Polymorphism refers to that solid matter has not with two or more different spaces arrangement mode, formation
With the phenomenon of the solid state of physicochemical properties.It is for the crystal formation research of active constituents of medicine (API) and medicine solid-state table
Levying has very important meaning in pharmacy industry.The same medicine of different crystal forms, it is in stability, solubility and bioavilability
Deng might have significant difference in terms of biochemical property, the effect of so as to influence medicine.If selected without assessing well
Optimal drug crystal forms are researched and developed, and the change of crystal formation may be produced in clinical late, so as to cause the change of medicine effect
And the extension of listing, and then produce huge economic loss.
In addition, how to develop the novel crystal forms of medicine, so as to evade patent protection of the original medicine company to crystal formation, carry
It is early to introduce imitation medicine to the market, and in recent years one it is most important the problem of, imitation medicine will be directly influenced and bulk drug is public
The market of department and international competitiveness.
It has been comparative maturity and deep valued neck that drug crystal forms, which are studied and are characterized in American-European pharmaceutical industry with the solid-state of medicine,
Domain, but pharmaceutical industry still belongs to the starting stage at home.API crystal form has a great impact to its physical and chemical properties of drugs, including
Dissolubility, stability, dispersion rate, metabolic stability and bioavilability etc..By the hygroscopicity, the chemistry that compare different crystal forms
Stabilization, physical state stability, machinability etc. are studied, and can be obtained and be selected highly preferred solid forms to enter the hand-manipulating of needle
Exploitation to property.
Ceritinib (Ceritinib) it is chemical entitled:5-Chloro-N2-(2-isopropoxy-5-methyl-4-
Piperidin-4-yl-phenyl)-N4- [2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-
Diamine, its chemical structural formula are as follows:
Ceritinib as anaplastic lymphoma kinase (ALK) inhibitor, its for receptor tyrosine kinase insulin by
A member in body superfamily, clinically it is mainly used in the treatment of kinds cancer at present.Ceritinib has polymorphism, such as
WO2012082972A etc. discloses A types and Type B Ceritinib crystal habit and preparation method thereof, and Ceritinib crystal formation medicine
Thing is as effective ingredient, the application in the disease for the treatment of anaplastic lymphoma kinase mediation.But due to Ceritinib water
Dissolubility is very poor, causes oral absorption poor, greatly limit its clinical practice.
The content of the invention
In view of the defects of above-mentioned prior art is present, the purpose of the present invention is to propose to a kind of c-type crystal formation of Ceritinib, energy
The crystal formation for the Ceritinib that crystal formation crystallinity is high, water solubility is high is accessed, so as to improve the oral bio of Ceritinib
Availability.
The present invention also aims to the preparation method for the c-type crystal formation for providing Ceritinib, the preparation method technological parameter
Simply, it is easily controlled, c-type crystal formation, and favorable reproducibility is easily prepared.
The present invention also aims to the application for the c-type crystal formation for providing Ceritinib.
The purpose of the present invention is achieved by the following technical programs:
The c-type crystal formation of a kind of Ceritinib, in the X-ray powder diffraction figure that the crystal formation is obtained using Cu-K alpha ray measurements
2 θ angles be 4.9 °, 9.4 °, 9.9 °, 12.2 °, 13.7 °, 14.2 °, 14.4 °, 14.9 °, 15.6 °, 16.5 °, 17.0 °,
There is characteristic peak at 17.7 °, 18.9 °, 20.6 °, 22.0 °, 25.0 °, 26.6 °, 25.9 ° and 28.5 °.
In the c-type crystal formation of above-mentioned Ceritinib, it is preferred that the c-type crystal formation is existed by differentia scanning calorimetry
About 100 DEG C -120 DEG C characteristic peaks for measuring heat release after first heat absorption, feature melting peak is measured at about 172.9 DEG C.
The present invention also provides a kind of preparation method of the c-type crystal formation of above-mentioned Ceritinib, and it includes:
Ceritinib sample is completely dissolved under room temperature or heating condition using solvent, obtains Ceritinib solution;
By Ceritinib solution, crystallisation by cooling, that is, the c-type for obtaining Ceritinib are brilliant under -50 DEG C to room temperature conditions
Type.
In above-mentioned preparation method, it is preferred that the solvent includes methanol, or the solvent include methanol and ethanol,
Isopropanol, isoamyl alcohol, acetone, MEK, acetonitrile, tetrahydrofuran, nitromethane, ethyl acetate, methyl tertiary butyl ether(MTBE), toluene,
The mixed solvent that one or more in methyl iso-butyl ketone (MIBK), ether, dichloromethane, chloroform, dioxane and water etc. are formed.
The present invention also provides the c-type crystal formation of above-mentioned Ceritinib in the disease as treatment anaplastic lymphoma kinase mediation
Application in the medicine of disease.
In above-mentioned application, it is preferred that the disease of the anaplastic lymphoma kinase mediation is drenched including Anaplastic large cell
It is bar knurl, non Hodgkin lymphom, Inflammatory myofibroblastic tumor, neuroblastoma, sarcoma, lung cancer, bronchiolar carcinoma, preceding
Row gland cancer, breast cancer, cancer of pancreas, human primary gastrointestinal cancers, colon and rectum carcinoma, colon cancer, Colon and rectum adenoma, thyroid cancer, liver cancer, in liver
Cholangiocarcinoma, hepatocellular carcinoma, adrenal, stomach cancer, glioma, gliablastoma, carcinoma of endometrium, melanin
It is knurl, kidney, carcinoma of renal pelvis, carcinoma of urinary bladder, carcinoma of uterine body, cervix cancer, carcinoma of vagina, oophoroma, Huppert's disease, cancer of the esophagus, white
Blood disease, acute myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, the cancer of the brain, oral cavity and pharynx cancer, laryngocarcinoma or small
Intestinal cancer.
The present invention also provides a kind of pharmaceutical composition, and it is wrapped the c-type crystal formation for the Ceritinib stated and can pharmaceutically connect
The carrier received.
Ceritinib novel crystal forms C crystal form of the present invention, can be through X-ray powder diffraction (XRPD), thermogravimetic analysis (TGA)
(TG), the solid-state approach such as differential scanning calorimetric analysis (DSC) and infrared (IR) characterizes.
The present invention protrusion effect be:
The c-type crystal formation crystallinity of the Ceritinib of the present invention is high, water solubility is high, so as to improve the mouth of Ceritinib
Take bioavilability;Its preparation method is simple, is easily controlled, and c-type crystal formation, favorable reproducibility is easily prepared;And the c-type is brilliant
Type can effectively treat the disease of anaplastic lymphoma kinase mediation as medicine.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of the c-type crystal formation of the Ceritinib of embodiment 1;
Fig. 2 is the differential scanning calorimetric thermogram of the c-type crystal formation of the Ceritinib of embodiment 1;
Fig. 3 is the thermogravimetic analysis (TGA) figure of the c-type crystal formation of the Ceritinib of embodiment 1;
Fig. 4 is the infrared spectrogram of the c-type crystal formation of the Ceritinib of embodiment 1;
Fig. 5 is the stripping curve of the Ceritinib bulk drug of embodiment 1 and c-type crystal formation;
Fig. 6 is average Drug-time curve after each six Oral Administration in Rats Ceritinib raw materials of 5 two groups of embodiment and c-type crystal formation.
Embodiment
In order to which technical characteristic, purpose and the beneficial effect of the present invention is more clearly understood, now to the skill of the present invention
Art scheme carry out it is described further below, but it is not intended that to the present invention can practical range restriction.Institute in following embodiments
Experimental method is stated, is conventional method unless otherwise specified;The reagent and material, unless otherwise specified, can be from business way
Footpath obtains.
Embodiment 1
The present embodiment provides a kind of c-type crystal formation of Ceritinib, the X-ray that the crystal formation is obtained using Cu-K alpha ray measurements
In powder diagram 2 θ angles be 4.9 °, 9.4 °, 9.9 °, 12.2 °, 13.7 °, 14.2 °, 14.4 °, 14.9 °, 15.6 °,
There are characteristic peak, such as Fig. 1 at 16.5 °, 17.0 °, 17.7 °, 18.9 °, 20.6 °, 22.0 °, 25.0 °, 26.6 °, 25.9 ° and 28.5 °
It is shown.
The c-type crystal formation of the Ceritinib of the present embodiment is measured by differentia scanning calorimetry at about 100 DEG C -120 DEG C
The characteristic peak of heat release, measures feature melting peak, as shown in Figure 2 at about 172.9 DEG C after first absorbing heat.
The thermogravimetic analysis (TGA) figure of the c-type crystal formation of the Ceritinib of the present embodiment, infrared spectrogram are as shown in Figure 3 and Figure 4.
The c-type crystal formation of the Ceritinib of the present embodiment is prepared by following method:
1.0g Ceritinibs are placed in conical flask, add methanol 50mL, using magnetic stirrer, 40 DEG C of water-baths add
Heat obtains Ceritinib solution to being completely dissolved;By Ceritinib solution place room temperature under the conditions of crystallisation by cooling, solid separate out after
Filtering, reduced pressure at room temperature.Obtain the c-type crystal formation that white crystalline powder 0.92g is Ceritinib, yield 92%.
Compared with the Ceritinib of the c-type crystal formation of the present embodiment is carried out into dissolution experiment with the bulk drug (A types crystal formation) bought.
5mg solid powders are respectively taken in 10mL deionized waters, magnetic agitation, mixing speed is 70 revs/min.Respectively at 20,40,60,
Sample within 80,100,120,150 and 180 minutes, solubility test is carried out with high performance liquid chromatography (HPLC).Solubility (contains in water
Amount) computational methods be area normalization method.
As a result as shown in figure 5, in deionized water, the solubility of C crystal form is 5 times of bulk drug after 3 hours, and solubility shows
Write and improve, show good water solubility.
Embodiment 2
The present embodiment provides a kind of c-type crystal formation of Ceritinib, and qualitative determination result is the same as embodiment 1.
The c-type crystal formation of the Ceritinib of the present embodiment is prepared by following method:
1.0g Ceritinibs are placed in conical flask, add methanol 50mL.Using magnetic stirrer, 40 DEG C of water-baths add
Heat obtains Ceritinib solution to being completely dissolved;Ceritinib solution is placed into 5 DEG C of refrigerator crystallisation by cooling.After solid separates out
Filtering, reduced pressure at room temperature.Obtain the c-type crystal formation that white crystalline powder 0.95g is Ceritinib, yield 95%.
Embodiment 3
The present embodiment provides a kind of c-type crystal formation of Ceritinib, and qualitative determination result is the same as embodiment 1.
The c-type crystal formation of the Ceritinib of the present embodiment is prepared by following method:
1.0g Ceritinibs are placed in conical flask, add methanol/acetone (volume ratio 2: 1) 50mL.Use magnetic agitation
Device stirs, and 40 DEG C of heating water baths obtain Ceritinib solution to being completely dissolved;Ceritinib solution is placed into 5 DEG C of refrigerator coolings
Crystallization.Solid filters after separating out, reduced pressure at room temperature.Obtain the c-type crystalline substance that white crystalline powder 0.93g is Ceritinib
Type, yield 93%.
Embodiment 4
The present embodiment provides a kind of c-type crystal formation of Ceritinib, and qualitative determination result is the same as embodiment 1.
The c-type crystal formation of the Ceritinib of the present embodiment is prepared by following method:
1.0g Ceritinibs are placed in conical flask, add methanol/tetrahydrofuran (volume ratio 4: 1) 50mL.Use magnetic force
Agitator stirs, and 50 DEG C of heating water baths obtain Ceritinib solution to being completely dissolved;Ceritinib solution is placed into 5 DEG C of refrigerators
Crystallisation by cooling.Solid filters after separating out, reduced pressure at room temperature.Obtain the c-type that white crystalline powder 0.93g is Ceritinib
Crystal formation, yield 93%.
Embodiment 5
It is dynamic that the c-type crystal formation for the Ceritinib that the present embodiment obtains to any one embodiment in embodiment 1-4 carries out medicine generation
Mechanical test.Pass through LC/MS/MS six SPF levels SD Oral Administration in Rats Ceritinibs raw materials each to two groups (A crystal formations, conventional) and c-type
Crystal formation carries out contrasting pharmacokinetics test:Calculated according to the body weight 200g of rat, every rat dosage is 4mg, i.e.,
20mg/kg, single oral dose administration.
0.5 after administration, 1,3,5,7,9,15,20,24h venous blood sampling 0.2mL, be placed in scribble heparin centrifugation examination
Guan Zhong, immediately under the conditions of 15000rpm, 5min is centrifuged, upper plasma is drawn, is placed in -20 DEG C of refrigerators and preserves, it is to be analyzed.Point
During analysis, respectively by plasma sample thaw at RT, after vortex mixes, precision takes the μ L of plasma sample 100, puts in tool plug test tube, adds
Acetonitrile 400 μ L, vortex mixing 1min, centrifugation 10min (15000rpm), vortex mixing, 20 μ L are taken to carry out LC/MS/MS analyses.
Analysis result is as shown in fig. 6, C of the Ceritinib novel crystal forms c-type crystal formation in rat bodymaxExist for raw material (A crystal formations)
C in rat bodymax1.5 times, it is seen that the c-type crystal formation of Ceritinib can significantly improve Ceritinib in vivo biology profit
Expenditure.
Therefore the c-type crystal formation crystallinity of the Ceritinib of the embodiment of the present invention is high, water solubility is high.So as to
Improve the oral administration biaavailability of Ceritinib;Its preparation method is simple, is easily controlled, and c-type crystal formation is easily prepared, and again
Existing property is good.
Claims (6)
1. a kind of c-type crystal formation of Ceritinib, in the X-ray powder diffraction figure that the crystal formation is obtained using Cu-K alpha ray measurements
2 θ angles be 4.9 °, 9.4 °, 9.9 °, 12.2 °, 13.7 °, 14.2 °, 14.4 °, 14.9 °, 15.6 °, 16.5 °, 17.0 °, 17.7 °,
There is characteristic peak at 18.9 °, 20.6 °, 22.0 °, 25.0 °, 26.6 °, 25.9 ° and 28.5 °.
2. the c-type crystal formation of Ceritinib according to claim 1, it is characterised in that the c-type crystal formation passes through differential scanning
The characteristic peak of heat release, feature melting peak is measured at 172.9 DEG C after thermometric analysis method measures first heat absorption at 100 DEG C -120 DEG C.
3. the preparation method of the c-type crystal formation of the Ceritinib described in claim 1 or 2, it includes:
Ceritinib sample is completely dissolved under room temperature or heating condition using solvent, obtains Ceritinib solution;
By Ceritinib solution under -50 DEG C to room temperature conditions crystallisation by cooling, obtain the c-type crystal formation of Ceritinib;
Wherein, the solvent includes methanol, the mixed solvent of methanol and acetone or the mixed solvent of methanol and tetrahydrofuran.
4. the c-type crystal formation of the Ceritinib described in claim 1 or 2 is in the disease as treatment anaplastic lymphoma kinase mediation
Medicine in application.
5. application according to claim 4, it is characterised in that:Between the disease of the anaplastic lymphoma kinase mediation includes
It is denatured large celllymphoma, non Hodgkin lymphom, Inflammatory myofibroblastic tumor, neuroblastoma, sarcoma, lung
Cancer, bronchiolar carcinoma, prostate cancer, breast cancer, cancer of pancreas, human primary gastrointestinal cancers, colon and rectum carcinoma, colon cancer, Colon and rectum adenoma, first shape
Gland cancer, liver cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, adrenal, stomach cancer, glioma, gliablastoma, uterus
Endometrial carcinomas, melanoma, kidney, kidney Meng cancer, carcinoma of urinary bladder, carcinoma of uterine body, cervix cancer, carcinoma of vagina, oophoroma, multiple marrow
Knurl, cancer of the esophagus, leukaemia, acute myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, the cancer of the brain, oral cavity and pharynx
Cancer, laryngocarcinoma or carcinoma of small intestine.
6. a kind of pharmaceutical composition, it includes the c-type crystal formation of the Ceritinib described in claim 1 or 2 and can pharmaceutically connect
The carrier received.
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KR20190022903A (en) | 2010-12-17 | 2019-03-06 | 노파르티스 아게 | Crystalline forms of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
WO2016081538A1 (en) * | 2014-11-18 | 2016-05-26 | Teva Pharmaceuticals International Gmbh | Solid state forms of ceritinib and salts thereof |
WO2016098070A1 (en) * | 2014-12-19 | 2016-06-23 | Novartis Ag | Crystalline form of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine |
WO2017152858A1 (en) * | 2016-03-11 | 2017-09-14 | 苏州晶云药物科技有限公司 | Crystal form of ceritinib and preparation method thereof |
CN113244236B (en) * | 2021-06-01 | 2023-02-03 | 上海市第一人民医院 | Application of ceritinib in preparation of medicine for treating thyroid-associated ophthalmopathy |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
CN103282359A (en) * | 2010-12-17 | 2013-09-04 | 诺华股份有限公司 | Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
CN104803908A (en) * | 2015-03-26 | 2015-07-29 | 药源药物化学(上海)有限公司 | Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride as well as preparation method and application of hydrate |
-
2015
- 2015-08-07 CN CN201510486961.2A patent/CN105061397B/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101616895A (en) * | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | Compound and composition as kinases inhibitor |
CN103282359A (en) * | 2010-12-17 | 2013-09-04 | 诺华股份有限公司 | Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine |
CN104262324A (en) * | 2010-12-17 | 2015-01-07 | 诺华股份有限公司 | Crystalline Forms Of 5-chloro-n2-(2-isopropoxy-5-methyl- 4-piperidin-4-yl-phenyl)-n4[2-(propane-2-sulfonyl)-phenyl] -pyrimidine-2,4-diamine |
CN104803908A (en) * | 2015-03-26 | 2015-07-29 | 药源药物化学(上海)有限公司 | Hydrate of 2-isopropoxy-5-methyl-4-(4-piperidyl) aniline dihydrochloride as well as preparation method and application of hydrate |
Non-Patent Citations (1)
Title |
---|
Crystalline form of 5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine;Anonymously;《IP.COM》;20141211;1-3 * |
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